Browse by author
Lookup NU author(s): Dr Stella Breininger
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2022 The AuthorsThe chemotherapy resistance of esophageal adenocarcinomas (EACs) is underpinned by cancer cell extrinsic mechanisms of the tumor microenvironment (TME). We demonstrate that, by targeting the tumor-promoting functions of the predominant TME cell type, cancer-associated fibroblasts (CAFs) with phosphodiesterase type 5 inhibitors (PDE5i), we can enhance the efficacy of standard-of-care chemotherapy. In ex vivo conditions, PDE5i prevent the transdifferentiation of normal fibroblasts to CAF and abolish the tumor-promoting function of established EAC CAFs. Using shotgun proteomics and single-cell RNA-seq, we reveal PDE5i-specific regulation of pathways related to fibroblast activation and tumor promotion. Finally, we confirm the efficacy of PDE5i in combination with chemotherapy in close-to-patient and in vivo PDX-based model systems. These findings demonstrate that CAFs drive chemotherapy resistance in EACs and can be targeted by repurposing PDE5i, a safe and well-tolerated class of drug administered to millions of patients world-wide to treat erectile dysfunction.
Author(s): Sharpe BP, Hayden A, Manousopoulou A, Cowie A, Walker RC, Harrington J, Izadi F, Breininger SP, Gibson J, Pickering O, Jaynes E, Kyle E, Saunders JH, Parsons SL, Ritchie AA, Clarke PA, Collier P, Mongan NP, Bates DO, Yacqub-Usman K, Garbis SD, Walters Z, Rose-Zerilli M, Grabowska AM, Underwood TJ
Publication type: Article
Publication status: Published
Journal: Cell Reports Medicine
Year: 2022
Volume: 3
Issue: 6
Online publication date: 21/06/2022
Acceptance date: 28/01/2022
Date deposited: 06/11/2023
ISSN (electronic): 2666-3791
Publisher: Cell Press
URL: https://doi.org/10.1016/j.xcrm.2022.100541
DOI: 10.1016/j.xcrm.2022.100541
PubMed id: 35732148
Altmetrics provided by Altmetric
